Infusion Reactions

Administration of rituximab products, including TRUXIMA, can result in serious,
including fatal, infusion reactions. Deaths within 24 hours of rituximab
infusion have occurred. Approximately 80% of fatal infusion reactions occurred
in association with the first infusion. Monitor patients closely. Discontinue
TRUXIMA infusion for severe reactions and provide medical treatment for Grade 3
or 4 infusion reactions [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS].

Severe Mucocutaneous
Reactions

Hepatitis B Virus (HBV)
Reactivation

HBV reactivation can occur in patients treated with rituximab
products, in some cases resulting in fulminant hepatitis, hepatic failure, and
death. Screen all patients for HBV infection before treatment initiation, and
monitor patients during and after treatment with TRUXIMA. Discontinue TRUXIMA
and concomitant medications in the event of HBV reactivation [see WARNINGS AND
PRECAUTIONS].

INDICATIONS

Non–Hodgkin’s Lymphoma (NHL)

TRUXIMA (rituximab-abbs) is
indicated for the treatment of adult patients with:

Relapsed or refractory, low-grade or follicular,
CD20-positive, B-cell NHL as a single agent.

Previously untreated follicular, CD20-positive, B-cell
NHL in combination with first line chemotherapy and, in patients achieving a
complete or partial response to a rituximab product in combination with
chemotherapy, as single-agent maintenance therapy.

DOSAGE AND ADMINISTRATION

Important Dosing Information

Administer only as an
Intravenous Infusion [see Administration and Storage].

Do not administer as an intravenous push or bolus.
TRUXIMA should only be administered by a healthcare professional with
appropriate medical support to manage severe infusion reactions that can be
fatal if they occur [see WARNINGS AND PRECAUTIONS].

Premedicate before each infusion [see Recommended Dose for Premedication and Prophylactic Medications].

Prior To First Infusion

Screen all patients for HBV infection by measuring HBsAg
and anti-HBc before initiating treatment with TRUXIMA [see WARNINGS AND
PRECAUTIONS]. Obtain complete blood counts including platelets (CBC) prior
to the first dose.

During TRUXIMA Therapy

In patients with lymphoid malignancies, during treatment
with TRUXIMA monotherapy, obtain complete blood counts (CBC) with differential
and platelet counts prior to each TRUXIMA course. During treatment with TRUXIMA
and chemotherapy, obtain CBC with differential and platelet counts at weekly to
monthly intervals and more frequently in patients who develop cytopenias [see ADVERSE
REACTIONS].

First Infusion: Initiate infusion at a rate of 50 mg/hr. In the absence
of infusion toxicity, increase infusion rate by 50 mg/hr increments every 30
minutes, to a maximum of 400 mg/hr.

Subsequent Infusions: Standard Infusion : Initiate infusion at a rate of 100 mg/hr. In the absence
of infusion toxicity, increase rate by 100 mg/hr increments at 30-minute
intervals, to a maximum of 400 mg/hr.

For Previously Untreated Follicular NHL

If patients did not experience a Grade 3 or 4 infusion
related adverse event during Cycle 1, a 90-minute infusion can be administered
in Cycle 2 with a glucocorticoidcontaining chemotherapy regimen.

Initiate at a rate of 20% of the total dose given in the
first 30 minutes and the remaining 80% of the total dose given over the next 60
minutes. If the 90-minute infusion is tolerated in Cycle 2, the same rate can
be used when administering the remainder of the treatment regimen (through
Cycle 6 or 8).

Patients who have clinically significant cardiovascular
disease or who have a circulating lymphocyte count ≥5000/mm³ before Cycle
2 should not be administered the 90-minute infusion [see Clinical Studies].

Interrupt the infusion or slow the infusion rate for
infusion reactions [see BOXED WARNING, WARNINGS AND PRECAUTIONS].
Continue the infusion at one-half the previous rate upon improvement of
symptoms.

Recommended Dose For Non-Hodgkin’s Lymphoma (NHL)

The recommended dose is 375 mg/m² as an intravenous
infusion according to the following schedules:

Previously Untreated, Follicular, CD20-Positive,
B-Cell NHL Administer on Day 1 of each cycle of chemotherapy, for up to 8 doses. In
patients with complete or partial response, initiate TRUXIMA maintenance eight
weeks following completion of a rituximab product in combination with
chemotherapy. Administer TRUXIMA as a single-agent every 8 weeks for 12 doses.

Non-progressing, Low-Grade, CD20-Positive, B-Cell NHL,
after first-line CVP chemotherapy Following completion of 6-8 cycles of CVP chemotherapy, administer
once weekly for 4 doses at 6-month intervals to a maximum of 16 doses.

Recommended Dose For Premedication And Prophylactic
Medications

Premedicate with acetaminophen and an antihistamine
before each infusion of TRUXIMA. For patients administered TRUXIMA according to
the 90-minute infusion rate, the glucocorticoid component of their chemotherapy
regimen should be administered prior to infusion [seeClinical Studies].

Administration And Storage

Use appropriate aseptic technique. Parenteral drug
products should be inspected visually for particulate matter and discoloration
prior to administration. TRUXIMA should be a clear to opalescent, colorless to
pale yellow solution. Do not use vial if particulates or discoloration is
present.

Administration

Withdraw the necessary amount of TRUXIMA and dilute to a
final concentration of 1 mg/mL to 4 mg/mL in an infusion bag containing either
0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP. Gently invert the bag
to mix the solution. Do not mix or dilute with other drugs. Discard any unused
portion left in the vial.

Storage

Diluted TRUXIMA solutions for infusion may be stored at
2°C to 8°C (36°F to 46°F) for 24 hours. Diluted TRUXIMA solutions for infusion
have been shown to be stable for an additional 24 hours at room temperature.
However, since TRUXIMA solutions do not contain a preservative, diluted
solutions should be stored refrigerated (2°C to 8°C). No incompatibilities
between TRUXIMA and polyvinylchloride or polyethylene bags have been observed.

HOW SUPPLIED

Dosage Forms And Strengths

Injection: TRUXIMA is a clear to opalescent, colorless to
pale yellow solution for intravenous infusion:

Clinical Trials Experience In Lymphoid Malignancies

Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in clinical practice. The data
described below reflect exposure to rituximab in 2783 patients, with exposures
ranging from a single infusion up to 2 years. Rituximab was studied in both
single-arm and controlled trials (n=356 and n=2427). The population included
1180 patients with low grade or follicular lymphoma, and 1603 patients with
other indications. Most NHL patients received rituximab as an infusion of 375
mg/m² per infusion, given as a single agent weekly for up to 8 doses, in
combination with chemotherapy for up to 8 doses, or following chemotherapy for
up to 16 doses.

The most common adverse reactions of rituximab (incidence
≥25%) observed in clinical trials of patients with NHL were infusion
reactions, fever, lymphopenia, chills, infection, and asthenia.

Infusion Reactions

In the majority of patients with NHL, infusion reactions
consisting of fever, chills/rigors, nausea, pruritus, angioedema, hypotension,
headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or
hypertension occurred during the first rituximab infusion. Infusion reactions
typically occurred within 30 to 120 minutes of beginning the first infusion and
resolved with slowing or interruption of the rituximab infusion and with
supportive care (diphenhydramine, acetaminophen, and intravenous saline). The
incidence of infusion reactions was highest during the first infusion (77%) and
decreased with each subsequent infusion. [see WARNINGS AND PRECAUTIONS].
In patients with previously untreated follicular NHL or another indication, who
did not experience a Grade 3 or 4 infusion reaction in Cycle 1 and received a
90-minute infusion of rituximab at Cycle 2, the incidence of Grade 3-4 infusion
reactions on the day of, or day after the infusion was 1.1% (95% CI [0.3%,
2.8%]). For Cycles 2-8, the incidence of Grade 3-4 infusion reactions on the
day of or day after the 90-minute infusion, was 2.8% (95% CI [1.3%, 5.0%]). [see
WARNINGS AND PRECAUTIONS, Clinical Studies].

Infections

Serious infections (NCI CTCAE Grade 3 or 4), including
sepsis, occurred in less than 5% of patients with NHL in the single-arm
studies. The overall incidence of infections was 31% (bacterial 19%, viral 10%,
unknown 6%, and fungal 1%). [see WARNINGS AND PRECAUTIONS].

In randomized, controlled studies where rituximab was
administered following chemotherapy for the treatment of follicular or
low-grade NHL, the rate of infection was higher among patients who received
rituximab.

Cytopenias And hypogammaglobulinemia

In patients with NHL receiving rituximab monotherapy,
NCI-CTC Grade 3 and 4 cytopenias were reported in 48% of patients. These
included lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), and
thrombocytopenia (2%). The median duration of lymphopenia was 14 days (range,
1-588 days) and of neutropenia was 13 days (range, 2-116 days). A
single occurrence of transient aplastic anemia (pure red cell aplasia) and two
occurrences of hemolytic anemia following rituximab therapy occurred during the
single-arm studies.

In studies of monotherapy, rituximab-induced B-cell
depletion occurred in 70% to 80% of patients with NHL. Decreased IgM and IgG
serum levels occurred in 14% of these patients.

Immunogenicity

As with all therapeutic proteins, there is a potential
for immunogenicity. The detection of antibody formation is highly dependent on
the sensitivity and specificity of the assay. Additionally, the observed
incidence of antibody (including neutralizing antibody) positivity in an assay
may be influenced by several factors including assay methodology, sample
handling, timing of sample collection, concomitant medications, and underlying
disease. For these reasons, comparison of the incidence of antibodies to
rituximab in the studies described below with the incidence of antibodies in
other studies or to other products may be misleading.

Using an ELISA assay, anti-rituximab antibody was
detected in 4 of 356 (1.1%) patients with low-grade or follicular NHL receiving
single-agent rituximab. Three of the four patients had an objective clinical
response.

Postmarketing Experience

The following adverse reactions have been identified
during post-approval use of rituximab. Because these reactions are reported
voluntarily from a population of uncertain size, it is not always possible to
reliably estimate their frequency or establish a causal relationship to drug
exposure.

Premedicate patients with an antihistamine and
acetaminophen prior to dosing. Institute medical management (e.g.
glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion
reactions as needed. Depending on the severity of the infusion reaction and the
required interventions, temporarily or permanently discontinue TRUXIMA. Resume
infusion at a minimum 50% reduction in rate after symptoms have resolved.
Closely monitor the following patients: those with pre-existing cardiac or
pulmonary conditions, those who experienced prior cardiopulmonary adverse
reactions, and those with high numbers of circulating malignant cells
(≥25,000/mm³). [see Cardiovascular Adverse Reactions, ADVERSE REACTIONS].

Severe Mucocutaneous Reactions

Mucocutaneous reactions, some with fatal outcome, can
occur in patients treated with rituximab products. These reactions include
paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis,
vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these
reactions has been variable and includes reports with onset on the first day of
rituximab exposure. Discontinue TRUXIMA in patients who experience a severe
mucocutaneous reaction. The safety of re-administration of TRUXIMA to patients
with severe mucocutaneous reactions has not been determined.

Hepatitis B Virus (HBV) Reactivation

Hepatitis B virus (HBV) reactivation, in some cases
resulting in fulminant hepatitis, hepatic failure and death, can occur in
patients treated with drugs classified as CD20-directed cytolytic antibodies,
including rituximab products. Cases have been reported in patients who are
hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg
negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation
also has occurred in patients who appear to have resolved hepatitis B infection
(i.e., HBsAg negative, anti-HBc positive and hepatitis B surface antibody
[anti-HBs] positive).

HBV reactivation is defined as an abrupt increase in HBV
replication manifesting as a rapid increase in serum HBV DNA levels or
detection of HBsAg in a person who was previously HBsAg negative and anti-HBc
positive. Reactivation of HBV replication is often followed by hepatitis, i.e.,
increase in transaminase levels. In severe cases increase in bilirubin levels,
liver failure, and death can occur.

Screen all patients for HBV infection by measuring HBsAg
and anti-HBc before initiating treatment with TRUXIMA. For patients who show
evidence of prior hepatitis B infection (HBsAg positive [regardless of antibody
status] or HBsAg negative but anti-HBc positive), consult with physicians with
expertise in managing hepatitis B regarding monitoring and consideration for
HBV antiviral therapy before and/or during TRUXIMA treatment.

Monitor patients with evidence of current or prior HBV
infection for clinical and laboratory signs of hepatitis or HBV reactivation
during and for several months following TRUXIMA therapy. HBV reactivation has
been reported up to 24 months following completion of rituximab therapy.

In patients who develop reactivation of HBV while on
TRUXIMA, immediately discontinue TRUXIMA and any concomitant chemotherapy, and
institute appropriate treatment. Insufficient data exist regarding the safety
of resuming TRUXIMA treatment in patients who develop HBV reactivation.
Resumption of TRUXIMA treatment in patients whose HBV reactivation resolves
should be discussed with physicians with expertise in managing HBV.

Progressive Multifocal Leukoencephalopathy (PML)

JC virus infection resulting in PML and death can occur
in rituximab product-treated patients with hematologic malignancies. The
majority of patients with hematologic malignancies diagnosed with PML received
rituximab in combination with chemotherapy or as part of a hematopoietic stem
cell transplant. Most cases of PML were diagnosed within 12 months of their
last infusion of rituximab.

Consider the diagnosis of PML in any patient presenting
with new-onset neurologic manifestations. Evaluation of PML includes, but is
not limited to, consultation with a neurologist, brain MRI, and lumbar
puncture.

Discontinue TRUXIMA and consider discontinuation or
reduction of any concomitant chemotherapy or immunosuppressive therapy in
patients who develop PML.

Infections

Serious, including fatal, bacterial, fungal, and new or
reactivated viral infections can occur during and following the completion of
rituximab product-based therapy. Infections have been reported in some patients
with prolonged hypogammaglobulinemia (defined as hypogammaglobulinemia >11
months after rituximab exposure). New or reactivated viral infections included
cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus,
West Nile virus, and hepatitis B and C. Discontinue TRUXIMA for serious
infections and institute appropriate anti-infective therapy. [see ADVERSE
REACTIONS]. TRUXIMA is not recommended for use in patients with severe,
active infections.

Cardiovascular Adverse Reactions

Cardiac adverse reactions, including ventricularfibrillation, myocardial infarction, and cardiogenic shock may occur in
patients receiving rituximab products. Discontinue infusions for serious or
life-threatening cardiac arrhythmias. Perform cardiac monitoring during and
after all infusions of TRUXIMA for patients who develop clinically significant
arrhythmias, or who have a history of arrhythmia or angina.

Renal Toxicity

Severe, including fatal, renal toxicity can occur after
rituximab product administration in patients with NHL. Renal toxicity has
occurred in patients who experience tumor lysis syndrome and in patients with
NHL administered concomitant cisplatin therapy during clinical trials. The
combination of cisplatin and a rituximab product is not an approved treatment
regimen. Monitor closely for signs of renal failure and discontinue TRUXIMA in
patients with a rising serum creatinine or oliguria. [see Tumor Lysis Syndrome (TLS)].

Bowel Obstruction And Perforation

Abdominal pain, bowel obstruction and perforation, in
some cases leading to death, can occur in patients receiving rituximab products
in combination with chemotherapy. In postmarketing reports, the mean time to
documented gastrointestinal perforation was 6 (range 1-77) days in
patients with NHL. Evaluate if symptoms of obstruction such as abdominal pain
or repeated vomiting occur.

Immunization

The safety of immunization with live viral vaccines
following rituximab product therapy has not been studied and vaccination with
live virus vaccines is not recommended before or during treatment.

Embryo-Fetal Toxicity

Based on human data, rituximab products can cause fetal
harm due to B-cell lymphocytopenia in infants exposed in-utero. Advise pregnant
women of the risk to a fetus. Females of childbearing potential should use
effective contraception while receiving TRUXIMA and for 12 months following the
last dose of TRUXIMA.

Severe Mucocutaneous Reactions

Advise patients to contact their healthcare provider
immediately for symptoms of severe mucocutaneous reactions, including painful
sores or ulcers on the mouth, blisters, peeling skin, rash, and pustules [see
WARNINGS AND PRECAUTIONS].

Hepatitis B Virus Reactivation

Advise patients to contact their healthcare provider
immediately for symptoms of hepatitis including worsening fatigue or yellow
discoloration of skin or eyes [see WARNINGS AND PRECAUTIONS].

Progressive Multifocal Leukoencephalopathy (PML)

Advise patients to contact their healthcare provider
immediately for signs and symptoms of PML, including new or changes in
neurological symptoms such as confusion, dizziness or loss of balance,
difficulty talking or walking, decreased strength or weakness on one side of
the body, or vision problems [see WARNINGS AND PRECAUTIONS].

Tumor Lysis Syndrome (TLS)

Advise patients to contact their healthcare provider
immediately for signs and symptoms of tumor lysis syndrome such as nausea,
vomiting, diarrhea, and lethargy [see WARNINGS AND PRECAUTIONS].

Infections

Advise patients to contact their healthcare provider
immediately for signs and symptoms of infections including fever, cold symptoms
(e.g., rhinorrhea or laryngitis), flu symptoms (e.g., cough, fatigue, body
aches), earache or headache, dysuria, oral herpes simplex infection, and
painful wounds with erythema and advise patients of the increased risk of
infections during and after treatment with TRUXIMA [see WARNINGS AND
PRECAUTIONS].

Renal Toxicity

Advise patients of the risk of renal toxicity. Inform
patients of the need for healthcare providers to monitor kidney function [see
WARNINGS AND PRECAUTIONS].

Bowel Obstruction And Perforation

Advise patients to contact their healthcare provider
immediately for signs and symptoms of bowel obstruction and perforation,
including severe abdominal pain or repeated vomiting [see WARNINGS AND
PRECAUTIONS].

Embryo-Fetal Toxicity

Advise a pregnant woman of the potential risk to a fetus.
Advise female patients that rituximab products can cause fetal harm if taken
during pregnancy and to use effective contraception during treatment with
TRUXIMA and for at least 12 months after the last dose of TRUXIMA. Advise
patients to inform their healthcare provider of a known or suspected pregnancy
[see WARNINGS AND PRECAUTIONS and Use In Specific Populations].

Lactation

Advise women not to breastfeed during treatment with
TRUXIMA and for 6 months after the last dose [see Use In Specific
Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No long-term animal studies have been performed to
establish the carcinogenic or mutagenic potential of rituximab products or to
determine potential effects on fertility in males or females.

Use In Specific Populations

Pregnancy

Risk Summary

Based on human data, rituximab products can cause adverse
developmental outcomes including B-cell lymphocytopenia in infants exposed
in-utero (see Clinical Considerations). In animal reproduction studies,
intravenous administration of rituximab to pregnant cynomolgus monkeys during
the period of organogenesis caused lymphoid B-cell depletion in the newborn
offspring at doses resulting in 80% of the exposure (based on AUC) of those
achieved following a dose of 2 grams in humans. Advise pregnant women of the
risk to a fetus.

Adverse outcomes in pregnancy occur regardless of the
health of the mother or the use of medications. The background risk of major
birth defects and miscarriage for the indicated populations is unknown. The
estimated background risk in the U.S. general population of major birth defects
is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Observe newborns and infants for signs of infection and
manage accordingly.

Data

Human data

Postmarketing data indicate that B-cell lymphocytopenia
generally lasting less than six months can occur in infants exposed to
rituximab in-utero. Rituximab was detected postnatally in the serum of infants
exposed in-utero.

Animal Data

An embryo-fetal developmental toxicity study was
performed on pregnant cynomolgus monkeys. Pregnant animals received rituximab
via the intravenous route during early gestation (organogenesis period; post
coitum days 20 through 50). Rituximab was administered as loading doses on post
coitum (PC) Days 20, 21 and 22, at 15, 37.5 or 75 mg/kg/day, and then weekly on
PC Days 29, 36, 43 and 50, at 20, 50 or 100 mg/kg/week. The 100 mg/kg/week dose
resulted in 80% of the exposure (based on AUC) of those achieved following a
dose of 2 grams in humans. Rituximab crosses the monkey placenta. Exposed
offspring did not exhibit any teratogenic effects but did have decreased
lymphoid tissue B cells.

A subsequent pre-and postnatal reproductive toxicity
study in cynomolgus monkeys was completed to assess developmental effects
including the recovery of B cells and immune function in infants exposed to
rituximab in utero. Animals were treated with a loading dose of 0, 15, or 75
mg/kg every day for 3 days, followed by weekly dosing with 0, 20, or 100 mg/kg
dose. Subsets of pregnant females were treated from PC Day 20 through
postpartum Day 78, PC Day 76 through PC Day 134, and from PC Day 132 through
delivery and postpartum Day 28. Regardless of the timing of treatment, decreased
B cells and immunosuppression were noted in the offspring of rituximab-treated
pregnant animals. The B-cell counts returned to normal levels, and immunologic
function was restored within 6 months postpartum.

Lactation

There are no data on the presence of rituximab products
in human milk, the effect on the breastfed child, or the effect on milk
production. However, rituximab is detected in the milk of lactating cynomolgus
monkeys, and IgG is present in human milk. Since many drugs including antibodies
are present in human milk, advise a lactating woman not to breastfeed during
treatment and for at least 6 months after the last dose of TRUXIMA due to the
potential for serious adverse reactions in breastfed infants.

Females And Males Of Reproductive Potential

Contraception

Females of childbearing potential should use effective
contraception while receiving TRUXIMA and for 12 months following treatment.

Pediatric Use

The safety and effectiveness of rituximab in pediatric
patients have not been established.

Hypogammaglobulinemia has been observed in pediatric
patients treated with rituximab.

Geriatric Use

Low-Grade Or Follicular Non-Hodgkin’s Lymphoma

Patients with previously untreated follicular NHL
evaluated in Study 5 were randomized to rituximab as single-agent maintenance
therapy (n=505) or observation (n=513) after achieving a response to rituximab
in combination with chemotherapy. Of these, 123 (24%) patients in the rituximab
arm were age 65 or older. No overall differences in safety or effectiveness
were observed between these patients and younger patients. Other clinical
studies of rituximab in low-grade or follicular, CD20-positive, B-cell NHL did
not include sufficient numbers of patients aged 65 and over to determine
whether they respond differently from younger subjects.

Pharmacodynamics

Non-Hodgkin’s Lymphoma (NHL)

In NHL patients, administration
of rituximab resulted in depletion of circulating and tissue-based B cells.
Among 166 patients in Study 1 (NCT000168740), circulating CD19-positive B cells
were depleted within the first three weeks with sustained depletion for up to 6
to 9 months post treatment in 83% of patients. B-cell recovery began at
approximately 6 months and median B-cell levels returned to normal by 12 months
following completion of treatment.

There were sustained and
statistically significant reductions in both IgM and IgG serum levels observed
from 5 through 11 months following rituximab administration; 14% of patients
had IgM and/or IgG serum levels below the normal range.

Pharmacokinetics

Non-Hodgkin’s Lymphoma (NHL)

Pharmacokinetics were characterized in 203 NHL patients
receiving 375 mg/m² rituximab weekly by intravenous infusion for 4 doses.
Rituximab was detectable in the serum of patients 3 to 6 months after
completion of treatment.

Based on a population
pharmacokinetic analysis of data from 298 NHL patients who received rituximab
once weekly or once every three weeks, the estimated median terminal
elimination half-life was 22 days (range, 6.1 to 52 days). Patients with higher
CD19-positive cell counts or larger measurable tumor lesions at pretreatment
had a higher clearance. However, dose adjustment for pretreatment CD19 count or
size of tumor lesion is not necessary. Age and gender had no effect on the
pharmacokinetics of rituximab.

Specific Populations

The pharmacokinetics of
rituximab products have not been studied in children and adolescents.

No formal studies were conducted to examine the effects
of either renal or hepatic impairment on the pharmacokinetics of rituximab
products.

Drug Interaction Studies

Formal drug interaction studies have not
been performed with rituximab products.

Clinical Studies

The safety and effectiveness of rituximab in relapsed,
refractory CD20+ NHL were demonstrated in 3 single-arm studies enrolling 296
patients.

Study 1

A multicenter, open-label, single-arm study was conducted
in 166 patients with relapsed or refractory, low-grade or follicular, B-cell
NHL who received 375 mg/m² of rituximab given as an intravenous infusion weekly
for 4 doses. Patients with tumor masses > 10 cm or with > 5000
lymphocytes/μL in the peripheral blood were excluded from the study.

Results are summarized in Table 2. The median time to
onset of response was 50 days.

Disease-related signs and symptoms (including B-symptoms)
resolved in 64% (25/39) of those patients with such symptoms at study entry.

Study 2

In a multicenter, single-arm study, 37 patients with
relapsed or refractory, low-grade NHL received 375 mg/m² of rituximab weekly
for 8 doses. Results are summarized in Table 2.

Study 3

In a multicenter, single-arm study, 60 patients received
375 mg/m² of rituximab weekly for 4 doses. All patients had relapsed or
refractory, low-grade or follicular, B-cell NHL and had achieved an objective
clinical response to rituximab administered 3.8-35.6 months (median 14.5
months) prior to retreatment with rituximab. Of these 60 patients, 5 received
more than one additional course of rituximab. Results are summarized in Table
2.

* Six of these patients are
included in the first column. Thus, data from 296 intent-to-treat patients are
provided in this table.
† Kaplan-Meier projected with observed range.
‡ “+” indicates an ongoing response.
§ Duration of response: interval from the onset of response to disease
progression.

Study 4

A total of 322 patients with previously untreated
follicular NHL were randomized (1:1) to receive up to eight 3-week cycles of
CVP chemotherapy alone (CVP) or in combination with rituximab 375 mg/m² on Day
1 of each cycle (R-CVP) in an open-label, multicenter study. The main outcome
measure of the study was progression-free survival (PFS) defined as the time
from randomization to the first of progression, relapse, or death.

Twenty-six percent of the study
population was >60 years of age, 99% had Stage III or IV disease, and 50%
had an International Prognostic Index (IPI) score ≥2. The results for PFS
as determined by a blinded, independent assessment of progression are presented
in Table 3. The point estimates may be influenced by the presence of
informative censoring. The PFS results based on investigator assessment of
progression were similar to those obtained by the independent review
assessment.

Study 5

An open-label, multicenter, randomized (1:1) study was
conducted in 1,018 patients with previously untreated follicular NHL who
achieved a response (CR or PR) to rituximab in combination with chemotherapy.
Patients were randomized to rituximab as single-agent maintenance therapy, 375
mg/m² every 8 weeks for up to 12 doses or to observation. Rituximab was
initiated at 8 weeks following completion of chemotherapy. The main outcome
measure of the study was progression-free survival (PFS), defined as the time
from randomization in the maintenance/observation phase to progression,
relapse, or death, as determined by independent review.

Of the randomized patients, 40%
were ≥60 years of age, 70% had Stage IV disease, 96% had ECOG performance
status (PS) 0-1, and 42% had FLIPI scores of 3–5. Prior to randomization
to maintenance therapy, patients had received R-CHOP (75%), R-CVP (22%), or
R-FCM (3%); 71% had a complete or unconfirmed complete response and 28% had a
partial response.

PFS was longer in patients
randomized to rituximab as single agent maintenance therapy (HR: 0.54, 95% CI:
0.42, 0.70). The PFS results based on investigator assessment of progression
were similar to those obtained by the independent review assessment.

Figure 1 : Kaplan-Meier Plot of IRC Assessed
PFS

Study 6

A total of 322 patients with previously untreated
low-grade, B-cell NHL who did not progress after 6 or 8 cycles of CVP
chemotherapy were enrolled in an open-label, multicenter, randomized trial.
Patients were randomized (1:1) to receive rituximab, 375 mg/m² intravenous
infusion, once weekly for 4 doses every 6 months for up to 16 doses or no
further therapeutic intervention. The main outcome measure of the study was
progression-free survival defined as the time from randomization to
progression, relapse, or death. Thirty-seven percent of the study population
was >60 years of age, 99% had Stage III or IV disease, and 63% had an IPI
score ≥2.

There was a reduction in the
risk of progression, relapse, or death (hazard ratio estimate in the range of
0.36 to 0.49) for patients randomized to rituximab as compared to those who
received no additional treatment.

Ninety-Minute Infusions In Previously
Untreated Follicular NHL And Another Indication

In Study 10, patients with previously untreated
follicular NHL (n=113) or another indication (n=250) were evaluated in a
prospective, open-label, multi-center, single-arm trial for the safety of
90-minute rituximab infusions. Patients with follicular NHL received rituximab
375 mg/m² plus CVP chemotherapy. Patients with another indication received
rituximab 375 mg/m² plus other chemotherapy agents. Patients with clinically
significant cardiovascular disease were excluded from the study. Patients were
eligible for a 90-minute infusion at Cycle 2 if they did not experience a Grade
3-4 infusion-related adverse event with Cycle 1 and had a circulating lymphocyte
count ≤ 5000/mm³ before Cycle 2. All patients were pre-medicated with
acetaminophen and an antihistamine and received the glucocorticoid component of
their chemotherapy prior to rituximab infusion. The main outcome measure was
the development of Grade 3-4 infusion reactions on the day of, or day after,
the 90-minute infusion at Cycle 2 [seeADVERSE REACTIONS].

Eligible patients received
their Cycle 2 rituximab infusion over 90 minutes as follows: 20% of the total
dose given in the first 30 minutes and the remaining 80% of the total dose
given over the next 60 minutes [seeDOSAGE AND ADMINISTRATION]. Patients
who tolerated the 90minute rituximab infusion at Cycle 2 continued to receive
subsequent rituximab infusions at the 90-minute infusion rate for the remainder
of the treatment regimen (through Cycle 6 or Cycle 8).

The incidence of Grade 3-4
infusion reactions at Cycle 2 was 1.1% (95% CI [0.3%, 2.8%]) among all
patients, 3.5% (95% CI [1.0%, 8.8%]) for those patients treated with R-CVP, and
0.0% (95% CI [0.0%, 1.5%]) for those patients treated with rituximab and other
chemotherapy agents. For Cycles 2-8, the incidence of Grade 3-4 infusion
reactions was 2.8% (95% CI [1.3%, 5.0%]). No acute fatal infusion reactions
were observed.

Medication Guide

PATIENT INFORMATION

TRUXIMA®
(trux-ee’-mah)
(rituximab-abbs) injection

What is the most important information I should know
about TRUXIMA?

TRUXIMA can cause serious side effects that can
lead to death, including:

Infusion reactions. Infusion reactions are very
common side effects of TRUXIMA treatment. Serious infusion reactions can happen
during your infusion or within 24 hours after your infusion of TRUXIMA. Your
healthcare provider should give you medicines before your infusion of TRUXIMA
to decrease your chance of having a severe infusion reaction.
Tell your healthcare provider or get medical help right away if you get any of
these symptoms during or after an infusion of TRUXIMA:

hives (red itchy welts) or rash

itching

swelling of your lips, tongue, throat or face

sudden cough

shortness of breath, difficulty breathing or wheezing

weakness

dizziness or feel faint

palpitations (feel like your heart is racing or
fluttering

chest pain

Severe skin and mouth reactions. Tell your
healthcare provider or get medical help right away if you get any of these
symptoms at any time during your treatment with TRUXIMA:

painful sores or ulcers on your skin, lips or in your
mouth

blisters

peeling skin

rash

pustules

Hepatitis B virus (HBV) reactivation. Before you
receive your TRUXIMA treatment, your healthcare provider will do blood tests to
check for HBV infection. If you have had hepatitis B or are a carrier of
hepatitis B virus, receiving TRUXIMA could cause the virus to become an active
infection again. Hepatitis B reactivation may cause serious liver problems
including liver failure, and death. You should not receive TRUXIMA if you have
active hepatitis B liver disease. Your healthcare provider will monitor you for
hepatitis B infection during and for several months after you stop receiving
TRUXIMA.
Tell your healthcare provider right away if you get worsening tiredness, or
yellowing of your skin or white part of your eyes, during treatment with
TRUXIMA.

Progressive Multifocal Leukoencephalopathy (PML). PML is a rare, serious brain infection caused by a virus that can happen in
people who receive TRUXIMA. People with weakened immune systems can get PML.
PML can result in death or severe disability. There is no known treatment,
prevention, or cure for PML.

Tell your healthcare provider right away if you have any
new or worsening symptoms or if anyone close to you notices these symptoms:

confusion

dizziness or loss of balance

difficulty walking or talking

decreased strength or weakness on one side of your body

vision problems

See “What are the possible side effects of TRUXIMA?”
for more information about side effects.

What is TRUXIMA?

TRUXIMA is a prescription medicine used to treat adults
with Non-Hodgkin's Lymphoma (NHL) alone or with other chemotherapy medicines.

It is not known if TRUXIMA is safe and effective in
children.

Before you receive TRUXIMA, tell your healthcare
provider about all of your medical conditions,including if you:

have had a recent vaccination or are scheduled to receive
vaccinations. You should not receive certain vaccines before or during
treatment with TRUXIMA.

are pregnant or plan to become pregnant. Talk to your healthcare
provider about the risks to your unborn baby if you receive TRUXIMA during
pregnancy.
Females who are able to become pregnant should use effective birth control
(contraception) during treatment with TRUXIMA and for 12 months after the last
dose of TRUXIMA. Talk to your healthcare provider about effective birth
control.
Tell your healthcare provider right away if you become pregnant or think that
you are pregnant during treatment with TRUXIMA.

are breastfeeding or plan to breastfeed. It is not known
if TRUXIMA passes into your breast milk. Do not breastfeed during treatment and
for at least 6 months after your last dose of TRUXIMA.

Tell your healthcare provider about all the medicines you
take, including prescription and over-thecounter medicines, vitamins, and
herbal supplements. Especially tell your healthcare provider if you take or
have taken:

If you are not sure if your medicine is one listed above,
ask your healthcare provider.

How will I receive TRUXIMA?

TRUXIMA is given by infusion through a needle placed in a
vein (intravenous infusion), in your arm. Talk to your healthcare provider
about how you will receive TRUXIMA. Your healthcare provider may prescribe
medicines before each infusion of TRUXIMA to reduce infusion side effects such
as fever and chills.

Your healthcare provider should do blood tests regularly
to check for side effects to TRUXIMA.

Before each TRUXIMA treatment, your healthcare provider
or nurse will ask you questions about your general health. Tell your healthcare
provider or nurse about any new symptoms.

What are the possible side effects of TRUXIMA?

TRUXIMA can cause serious side effects, including:

See “What is the most important information I should
know about TRUXIMA?”

Tumor Lysis Syndrome (TLS). TLS is caused by the fast
breakdown of cancer cells. TLS can cause you to have:

kidney failure and the need for dialysis treatment

abnormal heart rhythm

TLS can happen within 12 to 24 hours after an infusion of
TRUXIMA. Your healthcare provider may do blood tests to check you for TLS. Your
healthcare provider may give you medicine to help prevent TLS.

Tell your healthcare provider right away if you have any
of the following signs or symptoms of TLS:

nausea

diarrhea

vomiting

lack of energy

Serious infections. Serious infections can happen
during and after treatment with TRUXIMA, and can lead to death. TRUXIMA can
increase your risk of getting infections and can lower the ability of your
immune system to fight infections. Types of serious infections that can happen
with TRUXIMA include bacterial, fungal, and viral infections. After receiving
TRUXIMA, some people have developed low levels of certain antibodies in their
blood for a long period of time (longer than 11 months). Some of these people
with low antibody levels developed infections. People with serious infections
should not receive TRUXIMA. Tell your healthcare provider right away if you
have any symptoms of infection:

Heart problems. TRUXIMA may cause chest pain,
irregular heartbeats, and heart attack. Your healthcare provider may monitor
your heart during and after treatment with TRUXIMA if you have symptoms of
heart problems or have a history of heart problems. Tell your healthcare
provider right away if you have chest pain or irregular heartbeats during
treatment with TRUXIMA.

Kidney problems. TRUXIMA can cause severe kidney
problems that lead to death. Your healthcare provider should do blood tests to
check how well your kidneys are working.

Stomach and serious bowel problems that can sometimes
lead to death. Bowel problems, including blockage or tears in the bowel can
happen if you receive TRUXIMA with chemotherapy medicines. Tell your healthcare
provider right away if you have any severe stomach-area (abdomen) pain or
repeated vomiting during treatment with TRUXIMA.

Your healthcare provider will stop treatment with TRUXIMA
if you have severe, serious or life-threatening side effects.

The most common side effects of TRUXIMA include:

infusion reactions (see “What is the most important
information I should know about TRUXIMA?”)

infections (may include fever, chills)

body aches

tiredness

nausea

Other side effects with TRUXIMA include:

aching joints during or within hours of receiving an
infusion

more frequent upper respiratory tract infection

These are not all of the possible side effects with
TRUXIMA.

Call your doctor for medical advice about side effects.
You may report side effects to FDA at 1-800-FDA1088.

General information about the safe and effective use
of TRUXIMA.

Medicines are sometimes prescribed for purposes other
than those listed in a Medication Guide. You can ask your pharmacist or
healthcare provider for information about TRUXIMA that is written for
healthcare professionals.